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A biophysical study on molecular physiology of the uncoupling proteins of the central nervous system.

ABSTRACT: Mitochondrial inner membrane uncoupling proteins (UCPs) facilitate transmembrane (TM) proton flux and consequently reduce the membrane potential and ATP production. It has been proposed that the three neuronal human UCPs (UCP2, UCP4 and UCP5) in the central nervous system (CNS) play significant roles in reducing cellular oxidative stress. However, the structure and ion transport mechanism of these proteins remain relatively unexplored. Recently, we reported a novel expression system for obtaining functionally folded UCP1 in bacterial membranes and applied this system to obtain highly pure neuronal UCPs in high yields. In the present study, we report on the structure and function of the three neuronal UCP homologues. Reconstituted neuronal UCPs were dominantly helical in lipid membranes and transported protons in the presence of physiologically-relevant fatty acid (FA) activators. Under similar conditions, all neuronal UCPs also exhibited chloride transport activities that were partially inhibited by FAs. CD, fluorescence and MS measurements and semi-native gel electrophoresis collectively suggest that the reconstituted proteins self-associate in the lipid membranes. Based on SDS titration experiments and other evidence, a general molecular model for the monomeric, dimeric and tetrameric functional forms of UCPs in lipid membranes is proposed. In addition to their shared structural and ion transport features, neuronal UCPs differ in their conformations and proton transport activities (and possibly mechanism) in the presence of different FA activators. The differences in FA-activated UCP-mediated proton transport could serve as an essential factor in understanding and differentiating the physiological roles of UCP homologues in the CNS.

SUBMITTER: Hoang T

PROVIDER: S-EPMC4613710 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Primary central nervous system lymphoma (PCNSL) is a rare B-cell lymphoma of central nervous system, which is often found in immunocompromised patients. The common clinical treatment of PCNSL is methotrexate (MTX) and whole brain radiation therapy. With the development of tumour immunology research, the tumour microenvironment of PCNSL is characterised by abnormal expression of different immune signature molecules and patients with PCNSL may benefit from tumour immunotherapy. Methods: In our research, RNA-seq data from 82 PCNSL patients were collated by mining the microarray data from the GEO database. All samples were classified into three types related to tumour immune response by the Cibersort algorithm and consistent clustering. Differential analysis of genes was used to uncover 2 sets of differential genes associated with tumour immunity. The ICI scores of each sample were obtained by PCA algorithm, and the relationship between ICI scores and immune checkpoint expression, immunotherapy and drug sensitivity was investigated. Genes associated with ICI scores and their functional characteristics were investigated by WGCNA analysis and PPI analysis, based on the ICI scores of each sample. Results: The tumour microenvironment in PCNSL has a greater relationship with the tumour immune response. ICI scores obtained from 375 differential genes were associated with multiple immune responses in PCNSL. PCNSL patients with higher ICI scores had a better tumour microenvironment and were sensitive to immunotherapy and some small molecule drug. This study also identified 64 genes associated with ICI scores, which may serve as important therapeutic and prognostic targets for PCNSL. Conclusion: The presence of multiple immunosuppressive responses in the tumour microenvironment of PCNSL which suggested that improving the immune function of PCNSL patients through immunotherapy and targeted therapies can be an effective treatment for PCNSL. And the ICI score and associated genes may also provide a better predictor of the clinical use of immunotherapy.

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A biophysical study on molecular physiology of the uncoupling proteins of the central nervous system.

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